Project Summary Effective management of both acute and chronic pain continues to be an unmet need in medicine. Pain affects a large percentage of especially the older population. Besides the obvious impact on quality of life, pain has an enormous economic impact, both in terms of direct health care costs and in lost economic productivity. Pain signals are primarily transmitted through small-diameter, unmyelinated C fibers. Unfortunately, none of the current pain therapies selectively target this sub-population of fibers. Recently, we discovered that we can achieve a targeted block of these small unmyelinated fibers without affecting larger fibers by applying heat to the tissue, which could have highly significant implications for the treatment of pain. Our initial demonstrations utilized infrared (IR) lasers to heat the tissue through water absorption of the light. These acute demonstrations showed no signs of thermal damage (e.g., structural or functional deficits). Increasing the radiant exposure of the laser blocked larger and larger fibers in a dose-dependent fashion. Block of the smallest fibers, those carrying pain signals, can be achieved with minimal temperature increases (3-4 oC) and is lower than currently utilized with pulsed radiofrequency (RF) pain therapy (up to 5 oC). Since these demonstrations are recent, it is likely that further optimization will lower the thermal load to the tissue. A main goal of this grant will be to find the optimal method for inducing heat block in the pain fibers. Several thermal methods will be compared and contrasted including IR, pulsed RF, resistive heating, and focused ultrasound (FUS). In aim 1, we will utilize robust, invertebrate (Aplysia), unmyelinated nerve preparations to explore parameter space (e.g., geometry of the heating profile in the tissue) for each thermal modality in order to reduce thermal load and increase reproducibility and safety. Aim 2 will develop a Multiphysics model for understanding the interaction between thermal modalities and neuronal tissue. The third aim will translate the technology to vertebrates (rat and dog) and include further optimization of heat delivery and development of thermal nerve cuffs. A thermal approach that specifically targets pain fibers will significantly reduce side effects and avoid the risks of addiction with pharmacology. We have coined the name TAIN (Thermal Analgesia by Inhibition of Nerves) for this novel technology. The work in this proposal may lead to exciting improvements in novel modalities for pain treatment and provide the basis for subsequent chronic studies.